Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?
Abstract
:1. Amyotrophic Lateral Sclerosis (ALS): A Multifactorial Neurodegenerative Disease
2. The Role of Genetics in ALS Pathogenesis
3. The Role of Sex in ALS Pathogenesis
Key Points
Question: Are the Female and/or the Male Hormones Associated with ALS Development and Prognosis?
4. Interplay between Sex and Genetics in ALS Pathogenesis
5. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Ref. | Authors (date) | Methods | Findings |
---|---|---|---|
[92] | Hayes-Punzo et al. (2012) | preclinical study in SOD1G93A rats | no significant effect of gonadectomy on disease onset and progression in both sexes |
[96] | Kaneb et al. (2011) | preclinical study in SOD1G93A mice | metformin is unable to reduce pathology at any dose and has a dose-dependent negative effect on the clinical phenotype in female mice |
[91] | Li et al. (2012) | preclinical study in SOD1G93A rat neural progenitor cells (rNPCs) | SOD1G93A overexpression significantly reduces cell proliferation in male cells but not female cells |
[103] | Bame et al. (2012) | preclinical study in SOD1G93A mice | methionine sulfoximine treatment improves the survival of both male and female mice, but the effects are significantly greater on female mice; this effect is absent after ovariectomy or castration |
[95] | Eschbach et al. (2013) | clinical study of a German ALS cohort (n = 590 (237F, 353M)) and of an independent Swedish ALS (confirmation) cohort (n = 464 (196F, 268M)) preclinical study in SOD1G93A mice | deficiency in the co-activator PGC-1α, a regulator of the cellular response to metabolic demands, may influence age of onset and survival in a male-specific manner |
[102] | Cacabelos et al. (2014) | preclinical study in SOD1G93A mice | both survival and clinical evolution are dependent on dietary fatty acid unsaturation and gender, with high unsaturated diet leading to loss of the disease-sparing effect of the feminine gender |
[98] | Cacabelos et al. (2016) | preclinical study in SOD1G93A mice Neuro-2A cells expressing G93A mutant or non-mutated human SOD1 | ALS-associated SOD1 mutation leads to delayed mitochondrial dysfunction in female mice in comparison with males; overexpression of SOD1G93A in Neuro-2A cells reduced complex I function, and this loss of function is prevented by 17β-estradiol pretreatment |
[94] | Ohta et al. (2016) | preclinical study in SOD1G37R mice and double transgenic mice overexpressing CHGB species and mutant SOD1G37R; Neuro-2A cells expressing human chromogranin B (CHGB) P413L; clinical study of Japanese (n = 141), French/Canadian (n = 289), French (n = 527), and in Swedish (n = 453) cohorts | the expression of CHGB 413L allelic variant in SOD1G37R mice is related to pathological changes and earlier ALS onset, specifically in female mice; in humans, the sex-related effects of CHGB variants on ALS onset are still debated |
[99] | Riar et al. (2017) | preclinical study in SOD1G93A mice and Estrogen Receptor α (ERα)-knockout mice with the G93A-SOD1 mutation (ERaKO-G93A) | sex differences in the disease phenotype could be linked to differential activation of the mitochondrial intermembrane space mitochondrial unfolded protein response (IMS-UPRmt), probably related to ERα axis |
[93] | Yan et al. (2018) | preclinical study in SOD1G93A mice | ovariectomy is associated with earlier ALS onset and attenuated the anti-inflammatory and anti-apoptotic actions of estrogen in SOD1G93A transgenic mice |
[105] | Williams et al. (2013) | clinical study of Australian cohorts (FALS = 193; SALS = 559; HCs = 170) | gender-specific differences for age of onset in C9orf72-linked ALS: male subjects are more likely to express the disease at a younger age |
[9] | Rooney et al. (2017) | case-control, population-based/multicenter study (n = 5106 (2053F, 2872M) ALS patients) | interaction between gender and C9orf72 repeat expansions may have negative prognostic implications in men with spinal onset disease |
[10] | Trojsi et al. (2019) | case-control, multicenter study (n = 1324 (596F, 728M) ALS patients) | carrying the C9orf72 repeat expansion is an independent factor negatively impacting survival time in men but not in women |
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Trojsi, F.; D’Alvano, G.; Bonavita, S.; Tedeschi, G. Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link? Int. J. Mol. Sci. 2020, 21, 3647. https://doi.org/10.3390/ijms21103647
Trojsi F, D’Alvano G, Bonavita S, Tedeschi G. Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link? International Journal of Molecular Sciences. 2020; 21(10):3647. https://doi.org/10.3390/ijms21103647
Chicago/Turabian StyleTrojsi, Francesca, Giulia D’Alvano, Simona Bonavita, and Gioacchino Tedeschi. 2020. "Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?" International Journal of Molecular Sciences 21, no. 10: 3647. https://doi.org/10.3390/ijms21103647